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Significance Immune activation and inflammation are predictors of serious non-AIDS events even in virally suppressed HIV-1−infected individuals. This does not apply to HIV-2−infected patients, who experience a form of attenuated HIV-1 disease. Here, we show that the HIV-1 matrix protein 17 (p17) binds to and activates the common beta chain receptor (βCR). The βCR-activating epitope on p17 is expressed on the matrix protein of HIV-1 ancestors but not on that of HIV-2 and its ancestors. Our finding highlights this epitope as a signature tracing the HIV-1 evolutionary trajectory that may have represented a critical step to enhance the HIV-1 ancestors aggressiveness and early human-to-human transmission. Whether this functional epitope actually marks the pathogenic difference between HIV-1 and HIV-2 needs further investigation., The HIV-1 matrix protein p17 (p17) is a pleiotropic molecule impacting on different cell types. Its interaction with many cellular proteins underlines the importance of the viral protein as a major determinant of human specific adaptation. We previously showed the proangiogenic capability of p17. Here, by integrating functional analysis and receptor binding, we identify a functional epitope that displays molecular mimicry with human erythropoietin (EPO) and promotes angiogenesis through common beta chain receptor (βCR) activation. The functional EPO-like epitope was found to be present in the matrix protein of HIV-1 ancestors SIV originated in chimpanzees (SIVcpz) and gorillas (SIVgor) but not in that of HIV-2 and its ancestor SIVsmm from sooty mangabeys. According to biological data, evolution of the EPO-like epitope showed a clear differentiation between HIV-1/SIVcpz-gor and HIV-2/SIVsmm branches, thus highlighting this epitope on p17 as a divergent signature discriminating HIV-1 and HIV-2 ancestors. P17 is known to enhance HIV-1 replication. Similarly to other βCR ligands, p17 is capable of attracting and activating HIV-1 target cells and promoting a proinflammatory microenvironment. Thus, it is tempting to speculate that acquisition of an epitope on the matrix proteins of HIV-1 ancestors capable of triggering βCR may have represented a critical step to enhance viral aggressiveness and early human-to-human SIVcpz/gor dissemination. The hypothesis that the p17/βCR interaction and βCR abnormal stimulation may also play a role in sustaining chronic activation and inflammation, thus marking the difference between HIV-1 and HIV-2 in term of pathogenicity, needs further investigation.